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The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018. [ABSTRACT FROM AUTHOR]

Heidi Chwan Ko,1,* RJ Seager,2,* Sarabjot Pabla,2 Maria-Fernanda Senosain,2 Erik Van Roey,2 Shuang Gao,2 Kyle C Strickland,1,3 Rebecca Ann Previs,1,4 Michelle F Green,1 Maureen Cooper,1 Mary K Nesline,1 Stephanie B Hastings,1 Kobina Agyaful Amoah,1 Shengle Zhang,2 Jeffrey M Conroy,2 Taylor J Jensen,1 Marcia Eisenberg,5 Brian Caveney,5 Eric A Severson,1 Shakti Ramkissoon,1,6 Shipra Gandhi7 1Labcorp Oncology, Durham, NC, USA; 2Labcorp Oncology, Buffalo, NY, USA; 3Department of Pathology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 4Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC, USA; 5Labcorp, Burlington, NC, USA; 6Department of Pathology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA; 7Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA*These authors contributed equally to this workCorrespondence: Heidi Chwan Ko, Email Heidi.ko@labcorp.comBackground: The understanding of molecular characteristics of HER2-low breast cancer is evolving since the establishment of trastuzumab deruxtecan. Here, we explore the differences in expression patterns of immune-related genes in the tumor immune microenvironment (TME) and survival between HER2-low and HER2-zero breast cancers.Methods: Comprehensive genomic and immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on FFPE samples from 129 patients with advanced HER2-negative (immunohistochemistry (IHC) 0, 1+ or 2+ with negative ERBB2 amplification by in-situ hybridization) breast cancer. Both estrogen receptor (ER) and HER2 statuses were obtained from available pathology reports. mRNA expressions of immune biomarkers, except for PD-L1 IHC and TMB, were derived from RNA-seq. Statistical comparisons were performed using the Kruskal–Wallis or Wilcoxon Rank-Sum test or the two-sample test for equality of proportions with continuity correction (p≤ 0.05 for significance). Survival differences were calculated using Kaplan-Meier analysis (p≤ 0.05 for significance).Results: There were no significant differences in mRNA expressions of immune-related genes between HER2-low and HER2-zero breast cancers. However, HER2-low breast cancers were associated with a higher proportion of ER-positivity. When ER was analyzed along with HER2, we observed a significantly higher tumor immunogenic signature (TIGS) expression in HER2-zero/ER-negative tumors than in HER2-low/ER-positive tumors (p=0.0088). Similarly, lower expression of PD-L1 and T cell immunoglobulin and ITIM domain (TIGIT) mRNA was observed in HER2-low/ER-positive tumors when compared to HER2-zero/ER-negative tumors (p=0.014 and 0.012, respectively). Patients with HER2-low tumors had a longer median OS than those with HER2-zero tumors (94 months vs 42 months, p=0.0044).Conclusion: Patients with HER2-low breast cancer have longer survivals yet display no differences in immune-related gene expression when compared to those with HER2-zero cancers. The differences in survival can be attributed to the higher rate of ER-positivity seen in HER2-low breast cancers, compared to HER2-zero tumors.Keywords: HER2-low breast cancer, estrogen receptor, tumor immune microenvironment, immune checkpoint biomarkers, gene expression profiling, immune profiling

Timely and accurate identification of molecular alterations in solid tumors is essential for proper management of patients with advanced cancers. This has created a need for rapid, scalable comprehensive genomic profiling (CGP) systems that detect an increasing number of therapeutically-relevant variant types and molecular signatures. In this study, we assessed the analytical performance of the TruSight Oncology 500 High-Throughput assay for detection of somatic alterations from formalin-fixed paraffin-embedded tissue specimens. In parallel, we developed supporting software and automated sample preparation systems designed to process up to 70 clinical samples in a single NovaSeq 6000TM sequencing run with a turnaround time of <7 days from specimen receipt to report. The results demonstrate that the scalable assay accurately and reproducibly detects small variants, copy number alterations, microsatellite instability (MSI) and tumor mutational burden (TMB) from 40ng DNA, and multiple gene fusions, including known and unknown partners and splice variants from 20ng RNA. 717 tumor samples and reference materials with previously known alterations in 96 cancer-related genes were sequenced to evaluate assay performance. All variant classes were reliably detected at consistent and reportable variant allele percentages with >99% overall accuracy and precision. Our results demonstrate that the high-throughput CGP assay is a reliable method for accurate detection of molecular alterations in support of precision therapeutics in oncology. The supporting systems and scalable workflow allow for efficient interpretation and prompt reporting of hundreds of patient cancer genomes per week with excellent analytical performance. [ABSTRACT FROM AUTHOR]

Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

The article discusess a study conducted for examining how modes of climate variability contribute to crop production variance. It mentions that the lower fractions of global-scale soybean and wheat production variability result from substantial but offsetting climate-forced production anomalies. It also examines crop yields in the El Niño Southern Oscillation, Indian Ocean Dipole, and Atlantic variability.

Downscaled rainfall projections from 21 climate models from the CMIP5 archive are used to estimate future changes in rainfall erosivity in the continental Unites States. To estimate erosivity from rainfall in the absence of sub-hourly data, we have used both daily rainfall values and the modified Fournier Index -- which is based on monthly rainfall accumulation -- and derived the scaling relationship between rainfall and erosivity from observational estimates of both. The expectation of overall increase in erosivity is confirmed by these calculations, but a quantitative assessment is marred by large uncertainties. Specifically, the uncertainty in the method of estimation of erosivity is more consequential than that deriving from the spread in climate simulations, and leads to changes of uncertain sign in parts of the Southwest and Texas. We suggest that progress can be made by establishing a more reliable functional relationship between daily rainfall and erosivity. [ABSTRACT FROM AUTHOR]

An experimental parametric study of frequency selective guides, cylindrical structures constructed from square loop frequency selective surfaces, is presented. Square loop resonators on a thin dielectric substrate are used for the frequency selective surface. The guides are intended for use in applications where lightweight, low cost and narrow band radiating systems are required. Comments on the manufacture of the guides are made. Propagating and radiating regions of the structures are described. The effects of the thickness of the supporting substrate thickness are clearly displayed (shifting the resonant frequency), as is the dependence of the propagation loss at resonance on the number of resonators on the circumference of the guide. The thickness of the supporting substrate shows a smaller effect on loss. Frequency scanning in the radiation region is also clearly established. Complex propagation constants are obtained from the experimental results, using three methods. The 'short circuit radiation pattern' method gives results that correlate best with simulated results. The guides show guidance over a frequency band determined by the frequency selective surface resonance. They also demonstrate a frequency scanning radiation broadside to the guidance direction. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies have shown that obesity, typically measured by increased body mass index (BMI), is associated with an increased risk of gastroesophageal adenocarcinoma (GEAC), but the contributing molecular and immune mechanisms remain unknown. Since obesity is known to promote chronic inflammation, we hypothesized that obesity leads to inflammation-related immune dysfunction, which can be reversed by immune-modulating therapy. To test our hypothesis, we examined the clinical and molecular data from advanced GEAC patients. To this end, 46 GEAC tumors were evaluated for biomarkers representing tumor inflammation, cell proliferation, and PD-L1 expression. A CoxPH regression model with potential co-variates, followed by pairwise post hoc analysis, revealed that inflammation in the GEAC tumor microenvironment is associated with improved overall survival, regardless of BMI. We also observed a significant association between cell proliferation and progression-free survival in overweight individuals who received immune-modulating therapy. In conclusion, our data confirm the role of the immune system in the natural course of GEAC and its responses to immunotherapies, but do not support the role of BMI as an independent clinically relevant biomarker in this group of patients. [ABSTRACT FROM AUTHOR]

A three-dimensional model to calculate microwave power distribution in a radiative microwave interconnection system is described. The effect of a receiver antenna on the power available over the floor of a multichip module is noted. The requirement for a low-gain, and hence relatively small, antenna is shown. © 1998 John Wiley & Sons, Inc. Microwave Opt Technol Lett 18: 196–200, 1998. [ABSTRACT FROM AUTHOR]

A novel transition between a rigid-substrate and a flexible-substrate microstrip for use in wearable devices is described. The contact force between the conductors of the two microstrips is supplied by a pair of rectangular magnets. A simulation and measurement study carried out on a test jig comprising a back-to-back pair of such transitions demonstrated an insertion loss of better than 0.5 dB/transition can be achieved in the range of 0-3 GHz. [ABSTRACT FROM AUTHOR]

Two examples of fabric based frequency selective surfaces (FSSs) are presented. The FSSs are produced by using screen printing and weaving. Both measured and simulated data are presented showing excellent agreement and performance for the FSSs when compared with the simulated data. The performance of these samples points towards a useful screening technique using fabric hangings and wall coverings in a range of applications where temporary electromagnetic wave ingress or egress needs to be controlled. [ABSTRACT FROM AUTHOR]

A new approach to interfacing fabric based wireless systems to traditional electronics circuitry is presented. Measurements show possible insertion losses of the connector to be < 1 dB up to frequencies of about 4 GHz when electroplating has been used to increase the hook and loop conductivities. This reported work points towards an interconnection system that is flexible and will allow the removal and replacement of conventional electronics connected to textile based systems. [ABSTRACT FROM AUTHOR]